EP2413952B2 - Verbesserung bei der Förderung von gesundem Aufholwachstum - Google Patents

Verbesserung bei der Förderung von gesundem Aufholwachstum Download PDF

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EP2413952B2
EP2413952B2 EP10710358.2A EP10710358A EP2413952B2 EP 2413952 B2 EP2413952 B2 EP 2413952B2 EP 10710358 A EP10710358 A EP 10710358A EP 2413952 B2 EP2413952 B2 EP 2413952B2
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Prior art keywords
growth
infant
catch
protein
period
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French (fr)
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EP2413952B1 (de
EP2413952A1 (de
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Olivier Aprikian
Florence Blancher
Catherine Mace
Yassaman Shahkhalili
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Societe des Produits Nestle SA
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Societe des Produits Nestle SA
Nestle SA
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Priority to PL10710358T priority patent/PL2413952T3/pl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to the use of certain proteins to improve healthy growth and reduce the risk of development of insulin resistance as a consequence of uncontrolled (unhealthy) catch-up growth in infants and children and weight recovery in adults.
  • catch up growth should not be excessive as there are indications that periods of very rapid and/or very extensive catch up growth particularly during infancy may be linked with a risk of future obesity. It is also important that catch up growth is not accompanied by excessive fat deposition and hyperinsulinemia, as these features of catch-up growth may be linked with a risk of future obesity and diabetes.
  • phase of catch-up growth may correspond to a state of hyperinsulinaemia concomitant to a disproportionately faster rate of recovering body fat than that of lean tissue (Dulloo AG. Regulation of fat storage via suppressed thermogenesis: a thrifty phenotype that predisposes individuals with catch-up growth to insulin resistance and obesity. Hormone Research 65, Suppl 3: 90-7 (2006 )).
  • Insulin resistance occurs when the body fails to respond properly to the action of insulin produced by the pancreas. It occurs most frequently in adults, but is being noted increasingly in adolescents and younger children as well. The body attempts to overcome this resistance by secreting more insulin from the pancreas. The development of Type 2, or non-insulin dependent, diabetes occurs when the pancreas fails to sustain this increased insulin secretion.
  • IUGR semistarvation-refeeding and intra-uterine growth restriction
  • the present invention provides the use of a protein source comprising bovine casein proteins for the preparation of a nutritional composition for administration to an infant or young child undergoing a period of catch-up growth following a period of growth restriction during or after the period of catch-up growth so as to reduce the risk of development of insulin resistance or Type 2 diabetes later in the life of the infant or young child and so as to promote healthy growth in infant and young children, wherein the protein(s) are intact, wherein the bovine casein provides 100% by weight of the protein source, wherein the infant is a pre-term infant or an infant which has been subject to intra-uterine growth retardation, wherein the composition is an infant formula and has a protein content of less than 2.2 g/100 kcal, and wherein the energy density of the composition is between 620 and 640 kcal/litre.
  • the disclosure also shows a method of reducing the possibility that an infant or young child undergoing a period of catch-up growth following a period of growth restriction and thereby at risk of developing insulin resistance or Type 2 diabetes later in life will develop insulin resistance or Type 2 diabetes later in life comprising feeding to the at risk infant or young child during or after the period of catch-up growth a nutritional composition including a protein source comprising bovine casein proteins.
  • the disclosure also describes a nutritional solution based on bovine protein to reducing the risk of later diabetes development in adult during or after weight recovery following weight lost.
  • the bovine casein provides 100% by weight of the protein source.
  • Periods of catch-up growth may occur at any time in the life of an individual from birth to the age at which full physical stature is reached following a physical illness or injury or psychological trauma during which or as a result of which growth has been restricted.
  • Infants who are born prematurely or who are deemed to have been subject to intra-uterine growth retardation at birth seem to be particularly susceptible to grow rapidly immediately after birth and to be at elevated risk of such growth involving a disproportionately high rate of fat deposition as well as hyperinsulinaemia.
  • the present invention has particular utility in the care and nutrition of such infants.
  • period of catch-up growth means a rate of growth more rapid than that which would be expected in a healthy infant or young child of the same age by reference to published data including, as regards infants, the growth rates for breast fed infants set out in Acta Paediatrica, Vol 95, April 2006, Supplement 450 "WHO Child Growth Standards ";
  • peripheral of growth restriction means a rate of growth less rapid than that which would be expected in a healthy infant or young child of the same age by reference to published data including, as regards infants, the growth rates for breast fed infants set out in Acta Paediatrica, Vol 95, April 2006, Supplement 450 "WHO Child Growth Standards "; "infant” means a child under the age of 12 months; “intra-uterine growth restrication” or IUGR means any restriction in growth in utero of an individual having regard to gestational age and potential for growth of the individual; "protein content” means total content of proteinaceous material including free amino acids (if present); "young child” means a child between the age of 1 and 12 years.
  • unhealty or uncontrolled catch-up growth relates to excessive catch-up of body fat and excessive hyperinsulinemia that could constitute important mechanisms in the link between catch-up growth and susceptibility to later obesity and/or type 2 diabetes.
  • catch up growth is a controlled growth not inducing detrimental effects or reducing the risk of detrimental effects.
  • references to the energy density of the nutritional composition in a specified number of kilocalories per litre refer, in the context of powdered products, to the product after reconstitution according to the directions provided with the product.
  • the nutritional composition is suitable for consumption by infants and young children.
  • the composition may be a nutritionally complete formula such as an infant formula, a follow-on formula or a growing up milk.
  • the composition may be a juice drink or other chilled or shelf stable beverage or a soup, or baby foods for example.
  • the formula contains a protein source comprising bovine casein proteins, wherein the bovine casein provides 100% by weight of the protein source.
  • the protein source may additionally be supplemented with free amino acids if this is necessary to meet the minimum requirements for essential amino acid content. These requirements are published for example in EC Directive 2006/141/EC.
  • the proteins are intact proteins.
  • the protein content of the infant formula is less than 2.2g/100 kcal, preferably between 1.6 and 2.0g/100 kcal.
  • An infant formula for use according to the present invention contains a carbohydrate source.
  • Any carbohydrate source conventionally found in infant formulas such as lactose, saccharose, maltodextrin, starch and mixtures thereof may be used although the preferred source of carbohydrates is lactose.
  • the carbohydrate content of the infant formula is between 9 and 14 g/100 kcal.
  • An infant formula for use according to the present invention contains a source of lipids.
  • the lipid source may be any lipid or fat which is suitable for use in infant formulas. Suitable fat sources include palm olein, high oleic sunflower oil, linseed oil and high oleic safflower oil although a combination of linseed oil and high oleic safflower oil is preferred. Small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. In total, the lipid content may be between 4.4 and 6 g/100 kcal. Preferably, the ratio of linoleic acid (C18:2n-6): ⁇ -linolenic acid (C18:3n-3)in the lipid source is less than 7:1, more preferably between 7:1 and 5:1.
  • the infant formula will also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the infant formula include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended infant population.
  • the infant formula may contain emulsifiers and stabilisers such as soy lecithin, citric acid esters of mono- and di-glycerides, and the like.
  • the infant formula may optionally contain other substances which may have a beneficial effect such as probiotic lactic acid bacteria, prebiotic oligosaccharides, lactoferrin, nucleotides, nucleosides, and the like.
  • the formula may be prepared in any suitable manner. For example, it may be prepared by blending together the protein, the carbohydrate source, and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently about 50°C to about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture. The liquid mixture is then homogenised; for example in two stages.
  • the liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range of about 80°C to about 150°C for about 5 seconds to about 5 minutes, for example.
  • This may be carried out by steam injection, autoclave or by heat exchanger; for example a plate heat exchanger.
  • the liquid mixture may be cooled to about 60°C to about 85°C; for example by flash cooling.
  • the liquid mixture may then be again homogenised; for example in two stages at about 10 MPa to about 30 MPa in the first stage and about 2 MPa to about 10 MPa in the second stage.
  • the homogenised mixture may then be further cooled to add any heat sensitive components; such as vitamins and minerals.
  • the pH and solids content of the homogenised mixture are conveniently adjusted at this point.
  • the homogenised mixture is transferred to a suitable drying apparatus such as a spray drier or freeze drier and converted to powder.
  • the powder should have a moisture content of less than about 5% by weight.
  • the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.
  • composition of an infant formula for use according to the invention is given below:- Nutrient per 100kcal per litre Energy (kcal) 100 630 Protein (g) 1.5 9.45 (skimmed milk powder, modified sweet whey) free phenylalanine (mg) 30 189 free isoleucine (mg) 13.5 85 free tryptophan (mg) 4.9 30.9 free histidine (mg) 2.5 15.8 casein:whey ratio 40:60 40:60 Fat (g) 5.3 33.4 Linoleic acid (g) 0.7 4.4 ⁇ -Linolenic acid (mg) 106 668 DHA (mg) 11.5 72.5 ARA (mg) 11.5 72.5 Linoleic acid: ⁇ -Linolenic acid 6.5 6.5 Lactose (g) 11.6 73.1 Minerals and Electrolytes Na (mg) 25 158 K (mg) 89 561 Cl (mg) 64 403 Ca (mg) 64 403 P (mg) 32 202
  • This nutritional composition may be fed to an infant during a period of catch-up growth following a period of growth restriction as the sole source of nutrition from birth to the age of six months and subsequently as part of a mixed diet during the introduction of solid foods until weaning is complete at about the age of 12 months.
  • This example investigates the effect of protein type on body composition and insulin sensitivity using a rat model of semistarvation-refeeding.
  • mice All rats were obtained from Elevagc Janvier (France), caged singly in a temperature-controlled room (22 ⁇ 1°C) with a 12-h light/dark cycle, and maintained on a commercial chow diet (Kliba, Cossonay, Switzerland) consisting, by energy, of 24% protein, 66% carbohydrates, and 10% fat, and had free access to tap water.
  • micellar structure a micellar structure. All test diets were provided in isocaloric amounts (90 kcal per rat per day) which correspond to the average metabolisable energy intake of spontaneously growing male Sprague-Dawley rats in this weight range (220-350 g) under laboratory conditions. All diets were provided as a paste in plastic containers fixed to the rat cages - this form of diet delivery avoids spillage.
  • blood samples (about 0.5 ml) were taken from the tail vein, transferred on ice. The blood samples were then centrifuged, and the plasma frozen and stored at - 20°C for later assays of insulin (by ELISA, Crystal Chem) and glucose (using a Beckman glucose analyzer).
  • This example investigates the effect of protein type on growth and glucose tolerance and later basal glycaemia, and insulinaemia and insulin sensitivity (assessed by ratio of basal glucose to insulin) in a rat model of intrauterine growth restriction.
  • Non IUGR group is, chow diet (Kliba 3437)
  • IUGR Casein Semi-synthetic diet with casein (Table 2)
  • IUGR whey Semi-synthetic diet with whey (Table 2)
  • Table 2 PRODUITS Casein Whey g/100 g g/100 g Cornstarch 53 53 Caséine 20 Whey 20.3 Sucrose 10 10 Soybean oil 7 7 Cellulose 5 5 Min.
  • Mix AIN93 1.0 1.0 L- Cystine 0.3 Bitartr. choline 0.25 0.25 Tert-butylhydroquinone 0.014 0.014 Total (wet weight) 100 100 kcal/100 diet 365.0 365.00 % Energy Protein 20 20 CHO 64 64 Fat 16 16
  • Body composition body fat, lean mass and body water content
  • EchoMRI TM Echo Medical Systems, Houston, USA
  • IPGTT intraperitoneal glucose tolerance test
  • the blood samples were centrifuged and the plasma was frozen and stored at -40°C for subsequent insulin analysis by an ELISA method using kit from Crystal Chem.Inc (II,USA).
  • baseline glycaemia and insulinaemia were assessed by taking a blood sample from the tail vein at age of 119-120 days. The ratio of basal glucose to insulin ratio was calculated as an index of insulin sensitivity.
  • the body weight of IUGR casein pups was significantly higher than that of IUGR whey pups (and closer to the non IUGR control group) from age of 21 days up to the age of 90 days but not longer ( Figure 3C ).
  • the body compositions of all groups were similar during phase I & phase II.
  • Figure 4 shows that the glucose response to IPGTT (2-h area under curve) was significantly lower in the group fed with the casein diet compared to that fed the whey diet (p ⁇ 0.05). This beneficial effect of the casein diet on glucose tolerance was accompanied by a slight but not significant increase in insulin response (p>0.05).
  • Figure 5 shows that, at the age of 121 days when all groups were being fed the same diet, the group previously fed the casein based diet had significantly lower basal blood glycaemia ( Fig 5A ) and plasma insulinaemia ( Fig.5B ) compared to the group which had been fed the whey based diet (p ⁇ 0.05 in both cases).
  • the HOMA IR ( fig 5D ), index of insulin resistance was also significantly lower in IUGR animals which had been fed with casein diet relative to those which had been fed with the whey diet. Furthermore, the basal glucose to insulin ratio ( Fig. 5C ), index of insulin sensitivity, was also significantly higher in the IUGR animals which had been fed with the casein diet relative to those which have been with whey diet.

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Claims (5)

  1. Verwendung einer Proteinquelle, die Kuh-Caseinproteine umfasst, zur Herstellung einer Nährstoffzusammensetzung zur Verabreichung an einen Säugling oder ein Kleinkind, welcher/welches eine Periode des Aufholwachstums nach einer Periode der Wachstumsbeschränkung durchläuft, während oder nach der Periode des Aufholwachstums, um das Risiko der Entwicklung von Insulinresistenz oder Typ 2-Diabetes im weiteren Leben des Säuglings oder Kleinkinds zu reduzieren,
    wobei das/die Protein(e) intakt sind,
    wobei das Kuh-Casein zu 100 Gew.-% die Proteinquelle bereitstellt,
    wobei der Säugling ein frühgeborener Säugling oder ein Säugling mit intrauteriner Wachstumsretardierung ist,
    wobei die Zusammensetzung eine Säuglingsnahrung ist und einen Proteingehalt von weniger als 2,2 g/100 kcal aufweist,
    wobei die Energiedichte der Zusammensetzung zwischen 620 und 640 kcal/Liter liegt.
  2. Verwendung nach Anspruch 1, um das Wachstum in einem jungen Alter zu verbessern und das Risiko der Entwicklung von Insulinresistenz oder Typ 2-Diabetes im weiteren Leben des Säuglings oder Kleinkinds zu reduzieren.
  3. Verwendung nach einem der Ansprüche 1 oder 2, wobei die Nährstoffzusammensetzung ferner Lactose umfasst.
  4. Verwendung nach einem der Ansprüche 1 bis 3, wobei die Nährstoffzusammensetzung zusätzlich eine Lipidquelle umfasst, die Linolsäure (C18:2n-6) und α-Linolensäure (C18:3n-3) einschließt, so dass das Verhältnis von Linolsäure:α-Linolensäure zwischen 7:1 und 5:1 liegt.
  5. Verwendung nach einem der vorhergehenden Ansprüche, wobei die Zusammensetzung eine Säuglingsnahrung ist und einen Proteingehalt zwischen 1,6 und 2,0 g/100 kcal aufweist.
EP10710358.2A 2009-04-03 2010-03-26 Verbesserung bei der Förderung von gesundem Aufholwachstum Not-in-force EP2413952B2 (de)

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EP10710358.2A EP2413952B2 (de) 2009-04-03 2010-03-26 Verbesserung bei der Förderung von gesundem Aufholwachstum
PL10710358T PL2413952T3 (pl) 2009-04-03 2010-03-26 Polepszenie promowania zdrowego doganiania wzrostu

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EP09157244 2009-04-03
EP10710358.2A EP2413952B2 (de) 2009-04-03 2010-03-26 Verbesserung bei der Förderung von gesundem Aufholwachstum
PCT/EP2010/054032 WO2010112430A1 (en) 2009-04-03 2010-03-26 Improvement in promotion of healthy catch-up growth

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EP2413952A1 EP2413952A1 (de) 2012-02-08
EP2413952B1 EP2413952B1 (de) 2016-03-23
EP2413952B2 true EP2413952B2 (de) 2019-10-02

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US (1) US8846612B2 (de)
EP (1) EP2413952B2 (de)
CN (1) CN102378632A (de)
AU (1) AU2010230283B2 (de)
BR (1) BRPI1014065A2 (de)
CA (1) CA2755860A1 (de)
CL (1) CL2011002465A1 (de)
ES (1) ES2570461T5 (de)
MX (1) MX2011010454A (de)
MY (1) MY183275A (de)
PL (1) PL2413952T3 (de)
RU (1) RU2011144581A (de)
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EP2413952B1 (de) 2016-03-23
CN102378632A (zh) 2012-03-14
AU2010230283B2 (en) 2015-02-05
SG174355A1 (en) 2011-10-28
MX2011010454A (es) 2012-01-25
ES2570461T5 (es) 2020-04-03
CA2755860A1 (en) 2010-10-07
PL2413952T3 (pl) 2017-08-31
MY183275A (en) 2021-02-18
TW201039754A (en) 2010-11-16
BRPI1014065A2 (pt) 2016-04-12
EP2413952A1 (de) 2012-02-08
US20120021977A1 (en) 2012-01-26
US8846612B2 (en) 2014-09-30
WO2010112430A1 (en) 2010-10-07
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ES2570461T3 (es) 2016-05-18
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